The present invention relates to the preparation of dosage units for delivering bio-affecting agents, e.g., compressed tablets, and, in particular, relates to improved methods of manufacturing such units, as well as improved ingredients therefor.
Compressed tablets are prepared by compressing a formulation containing a medicinal substance or drug and other ingredients, such as excipients selected for properties which enhance the production and use of the tablet. There are currently three known basic methods for preparing tablet granulations. These are wet granulation, dry granulation and direct compression. Both wet and dry granulations involve the formation of an agglomerate for feeding to a die cavity. Direct compression usually involves compressing a powder blend of an active ingredient with suitable excipients.
The preparation of formulations for tableting by wet granulation is the oldest method and still the most widely used. Wet granulation involves many steps, including: milling of drugs and excipients, mixing of the milled powders, preparation of binder solution, mixing of the milled powders, preparation of binder solution, mixing of binder solution with powder mixture to form a wet mass, coarse screening of the wet mass using 6-12 mesh screens, drying of moist granules, screening of dry granules with lubricant and disintegrant, and tablet compression.
Wet granulation is an expensive process because it requires many processing steps and involves considerable material handling equipment. Consequently, the process requires both energy and substantial space which should be environmentally controlled.
Dry granulation refers to the granulation of a powder mixture by compression without the use of heat and solvent. Dry granulation is used when wet granulation is not available because the drug is sensitive to moisture or heat.
Two methods are used for dry granulation. One method is slugging, where the powder is precompressed on a heavy-duty tablet press, and the resulting tablets or slugs are milled to yield the granulation. The other method is precompression of the powder with pressure rolls using a compactor.
Dry granulation has many disadvantages. It requires a specialized heavy-duty tablet press to form the slug; it does not permit uniform color distribution as can be achieved with wet granulation, where dye can be incorporated into the binder liquid; the pressure roll press cannot be used with insoluble drugs because this may retard the dissolution rate; and the process tends to create dust thereby increasing the potential for cross-contamination.
Direct compression tableting has the least amount of steps. Direct compression is used in a process by which tablets are compressed directly from powder blends of the active ingredient and suitable excipients (including fillers, disintegrants, and lubricants) which are included in the mix to provide uniform flow into the die cavity and form a firm solid compression tablet. No pretreatment of the powder blends by wet or dry granulation procedures is necessary.
Although it has considerably fewer steps than either wet or dry granulation processes, direct compression also has many technological limitations. These limitations include primarily obtaining sufficient flow, and obtaining bonding of particles to form a strong compressed tablet. Low-dose drugs are difficult to blend, that is, uniform distribution of the drug is not easily attained and unblending sometimes occurs during the compression stage. High-dose drugs do not lend themselves to direct compression because of poor flowability and poor compressibility. A typical example would be some of the antacid drugs, such as aluminum hydroxide and magnesium carbonate.
When direct compression is used the choice of excipients is extremely critical. It is desirable that when using direct compression fillers and binders possess both compressibility and fluidity. In addition to compressibility failures, the process of direct compression also has disadvantages in the area of blending. Direct compression blends are subject to unblending in post blending handling steps. Differences in particle size because of differences in density between drug and excipient particles may also lead to unblending in the hopper or feedframe on the tablet press.
A disadvantage of all prior art process is the production of fines usually associated with making compression tablets. In the prior art, preparation of particles for formulation of tablets by compression results in a noticeable amount of fines, i.e., very tiny particles on the order of 150 microns and less. Fines interfere with operation of apparatus for feeding tableting machines as well as the operation of the tableting machines. Often, it is necessary to conduct tablet production in a facility which is environmentally controlled to eliminate or reduce the fines. This adds to the cost of production of the tablets.
Moreover, a percentage of the non-compressed particulate is lost during production because there are fines dispersed and cannot be recaptured, and because some of the fines are not capable of being recovered for recycle.
It is desirable to provide a method for direct compression tablet manufacturing which includes advantages of wet and dry granulation and traditional direct compression but does not have the disadvantages associated therewith.
In commonly owned U.S. Pat. No. 4,855,326 to Fuisz, the inventor has previously disclosed that a fiber form of medicament-bearing product can be compacted to form a sheet-like body. He cautions, however, that the compact body cannot be squeezed too much for fear of breaking the fibrous mass. There is no indication to form a compressed tablet as a medicinal dosage form.
Similarly, in U.S. Pat. No. 4,873,085 a spun fibrous cosmetic is disclosed as well as a compacted form of sugar fibers to form a sheet-like body which can be handled more readily. There is no indication to form a compressed tablet.
In U.S. Pat. No. 4,997,856, a wafer-like structure is disclosed in which a medicament is distributed on or through spun fibers which are then chopped by passing through a conventional "food grinder" (Hobart hamburger grinder). The enclosed volume of the end product is less than 30%, and preferably less than 15%, of the as-spun volume of floss. There is no mention in the '856 disclosure to form a compressed tablet.
The use of compacted spun fibers in the same sense as in the patents mentioned above is also disclosed in U.S. Pat. No. 5,034,421 and U.S. Pat. No. 5,096,492. None of these disclosures suggest formation of a compressed tablet.
Commonly-owned, copending U.S. application Ser. No. 08/194,682 filed Feb. 10, 1994 discloses a method for making edible units and product therefrom made by compressing shearform matrix masses sufficiently to form a comestible compression unit. Commonly-owned copending U.S. application Ser. No. 08/259,258 filed Jun. 14, 1994 discloses a method for preparing a quick-dissolve comestible unit by initiating crystallization of shearform matrix and combining with an additive, either before or after initiating crystallization, to form flowable, compactible micro-particulates and then subjecting the result micro-particulates to compacting, and the product therefrom. Commonly-owned copending U.S. application Ser. No. 08/259,496 filed Jun. 14, 1994 discloses a method of preparing a rapidly dissolving comestible unit by mixing uncured shearform matrix and an additive, molding a unit dosage form, and curing the matrix in the molded condition, and the product therefrom.
The above-identified parent application, which is incorporated herein by reference, describes a method for preparing discrete particles and the product resulting from the inventive method. Particles resulting from this method have highly consistent size and shape, which is substantially spheroidal. Thus, the disclosed method is highly efficient and predictable.
As a result of the consistent size and substantially spheroidal shape, the product has been found to have excellent flow properties. The flow property of a substance as used herein means the ability of the substance to flow. A mass of material can be made to flow by tilting the surface on which a quantity of the material results until it moves under the force of gravity in a direction away from the "at rest" position. A substance with good flow properties will move easily and evenly away from the "at rest" position. Such a material is easily utilized in processing apparatus for preparing compressed tablets, capsules, etc. Substances without good flow properties, do not readily flow, and generally do not move in an even condition. Such substances generally are transported in the form of clumps or uneven masses from the "at rest" position.
It is believed the unique properties of the product set forth in the parent application can be used to improve dosage units prepared by traditional tableting methods.
The present invention is, therefore, intended to overcome the shortcomings found in traditional tablet-making procedures, and to provide a significantly improved method of making tablets. These and other objects of the present invention will be realized by those skilled in the art in view of the following disclosure.